Oxidative stress causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and aging-related metabolic diseases. However, the molecular mechanisms underlying the pathogenesis remain poorly elucidated. We recently identified a novel pathway by which oxidative stress causes mitochondrial dysfunction in metabolic diseases. This pathway is mediated by ALCAT1, an acyl-CoA dependent acyltrasferase required for remodeling of cardiolipin (CL). CL is a unique mitochondrial phospholipid required for oxidative phosphorylation, fatty-acid oxidation, and mitochondrial dynamics. Among all the targets of reactive oxygen species (ROS), CL is most sensitive to oxidative damage of its four fatty acyl chains due to their high content in polyunsaturated fatty acids and exclusive location in mitochondria. Oxidized CL serves as a new source of ROS, initiating a self-destruction process known as “CL peroxidation” which has been implicated in mitochondrial etiology of metabolic aging-related diseases. Our work shows that ALCAT1 catalyzes the pathological remodeling of CL with fatty acyl chains that are highly sensitive to lipid peroxidation, leading to CL depletion and mitochondrial dysfunction. In support for a key role of the enzyme in mitochondrial etiology of age-related metabolic diseases, ALCAT1 expression is induced by ROS in obesity and diabetic complications, triggering a vicious cycle of oxidative stress, CL peroxidation, and mitochondrial dysfunction. Consequently, ablation of ALCAT1 in mice prevents the onset of several aging-related metabolic diseases, including diet-induced obesity (DIO), type 2 diabetes, fatty liver diseases, cardiomyopathy, and diabetic complications. Additionally, ALCAT1 deficiency significantly improves the mitochondrial quality control process by abrogating defective mitochondrial fusion and autophagy, two common defects associated with obesity. Together, these findings identify ALCAT1 as a key regulator of the “mitochondrial free radical aging clock” proposed by Denham Harman more than 60 years ago.